Chronic sleep deprivation induces ovarian ferroptosis and premature ovarian insufficiency linked to IL-17 signaling.

OBJECTIVE

Sleep deprivation (SD) disrupts female reproductive homeostasis, yet the mechanisms linking chronic sleep loss to premature ovarian insufficiency (POI) remain poorly defined.

METHODS

We analyzed sleep patterns and menopause timing in 147,814 UK Biobank women using multivariable logistic regression. We established a chronic SD mouse model and performed integrated multi-omics profiling, including serum proteomics and ovarian RNA sequencing, with pharmacological rescue using the ferroptosis inducer Erastin and inhibitor Ferrostatin-1.

RESULTS

Healthier sleep patterns were associated with reduced premature menopause risk (OR = 0.466, 95% CI: 0.263-0.826 for highest vs. lowest score). SD mice showed disrupted estrous cyclicity, elevated FSH, decreased AMH and E2, and accelerated ovarian reserve depletion. Multi-omics analysis revealed systemic inflammation (elevated IL-1α and IL-6) and ovarian enrichment of the IL-17 and ferroptosis pathways. Erastin recapitulated major SD-induced ovarian defects, whereas Ferrostatin-1 partially rescued the phenotype, establishing ferroptosis as a critical mediator. IL-17A and IL-17RA were upregulated and co-localized with ferroptosis markers in the ovarian stroma, nominating IL-17 signaling as a candidate upstream regulator.

CONCLUSION

Our findings establish ovarian ferroptosis as a key pathogenic mechanism linking chronic sleep deprivation to POI, and highlight sleep quality as a modifiable factor for preserving ovarian health.